Adenosine and cerebral ischemia: therapeutic future or death of a brave concept?

Lubitz, Dag K.J.E. Von

doi:10.1016/s0014-2999(99)00135-1

Cited by 126 publications

(82 citation statements)

References 231 publications

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“…Under pathological conditions, such as ischemia, stroke and seizure, the extracellular adenosine concentration is increased by 30-100 times that in the normal brain. Glia and neurons release adenosine and adenine nucleotides that may be converted into adenosine into the extracellular space (Cunha et al, 1996;Cunha, 2001;Mitchell et al, 1993;Parkinson and Xiong, 2004;Parkinson et al, 2005;von Lubitz, 1999). Therefore, adenosine could exert expanded neuroprotective effect in injured brain.…”

Section: Discussionmentioning

confidence: 99%

Adenosine induces hemeoxygenase‐1 expression in microglia through the activation of phosphatidylinositol 3‐kinase and nuclear factor E2‐related factor 2

Min

Kim

Jou

et al. 2008

Glia

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Adenosine, a purine nucleoside, has been reported to suppress the inflammatory responses of microglia in the brain. However, the underlying mechanisms of its anti-inflammatory action are unclear at present. Here we show that adenosine reduces the increase in intracellular reactive oxygen species (ROS) through expression of an antioxidant enzyme, hemeoxygenase-1 (HO-1). The H 2 O 2 -induced intracellular ROS level was significantly low in microglia pretreated with adenosine for 3-6 h, compared with that in untreated cells. Adenosine induced HO-1 mRNA and protein expression within 3 h, which was maintained for up to 12 h. Nuclear factor E2-related factor 2 (Nrf2), a transcription factor, and phosphatidylinositol 3-kinase (PI3K) and Akt pathways appear to mediate HO-1 expression. In response to adenosine, Nrf2 translocated from the cytosol to nuclei, and bound to the antioxidant response element (ARE). Adenosine enhanced HO-1 promoter activity in an ARE-dependent manner. Moreover, the nucleoside stimulated Akt phosphorylation, and suppressors of PI3K (LY294002 and wortmannin) reduced adenosine-induced HO-1 expression. However, we propose that the effects of adenosine are independent of adenosine receptors, since agonists and antagonists of A1, A2a, and A3 had little effect on the regulation of intracellular ROS and HO-1 expression. Our results collectively suggest that adenosine acts as an endogenous regulator of brain inflammation via modulation of microglial ROS production. V

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Section: Discussionmentioning

confidence: 99%

Adenosine induces hemeoxygenase‐1 expression in microglia through the activation of phosphatidylinositol 3‐kinase and nuclear factor E2‐related factor 2

Min

Kim

Jou

et al. 2008

Glia

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“…The first major drawback is due to the profound cardiovascular effects of A 1 R agonists (e.g., [178,179]), which are most worrying because A 1 R agonists have a poor brain permeability [180,181]. The second limitation is related to the short Fwindow of opportunity_ of A 1 R agonists, which is limited to a few hours, at most, after the initiation of the brain insult (reviewed in [171,173,174]; but see [182]). This is aggravated by the fact that is not conceivable to administer A 1 R agonists chronically (as a preventive strategy) because it causes an effect inversion, i.e.…”

Section: Modification Of Adenosine Metabolism On Stressful Conditionsmentioning

confidence: 99%

“…Likewise, several studies showed that short periods of brain ischemia, which also trigger a robust increase in the extracellular levels of adenosine ( [121]; reviewed in [172]), produce a long-lasting decrease in the density of A 1 Rs in several brain regions (e.g., [200Y202]). Again, this hypoxia-induced homologous desensitization of A 1 Rs [203] is accompanied by a loss of efficiency of A 1 R agonists when applied more than one hour after the hypoxia period (reviewed in [171,173,174]; but see [182]). This homologous desensitization of A 1 Rs has also been documented in other situations which trigger the release of adenosine.…”

Section: Modification Of Adenosine Metabolism On Stressful Conditionsmentioning

confidence: 99%

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

Cunha

2005

Purinergic Signalling

484

432

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Adenosine is a neuromodulator that operates via the most abundant inhibitory adenosine A 1 receptors (A 1 Rs) and the less abundant, but widespread, facilitatory A 2A Rs. It is commonly assumed that A 1 Rs play a key role in neuroprotection since they decrease glutamate release and hyperpolarize neurons. In fact, A 1 R activation at the onset of neuronal injury attenuates brain damage, whereas its blockade exacerbates damage in adult animals. However, there is a down-regulation of central A 1 Rs in chronic noxious situations. In contrast, A 2A Rs are up-regulated in noxious brain conditions and their blockade confers robust brain neuroprotection in adult animals. The brain neuroprotective effect of A 2A R antagonists is maintained in chronic noxious brain conditions without observable peripheral effects, thus justifying the interest of A 2A R antagonists as novel protective agents in neurodegenerative diseases such as Parkinson's and Alzheimer's disease, ischemic brain damage and epilepsy. The greater interest of A 2A R blockade compared to A 1 R activation does not mean that A 1 R activation is irrelevant for a neuroprotective strategy. In fact, it is proposed that coupling A 2A R antagonists with strategies aimed at bursting the levels of extracellular adenosine (by inhibiting adenosine kinase) to activate A 1 Rs might constitute the more robust brain neuroprotective strategy based on the adenosine neuromodulatory system. This strategy should be useful in adult animals and especially in the elderly (where brain pathologies are prevalent) but is not valid for fetus or newborns where the impact of adenosine receptors on brain damage is different.Abbreviations: Ab -b-amyloid peptide; A 1 Rs -A 1 receptors; A 2A Rs -A 2A

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“…119,123,129 One of the main hurdles is that A1 receptors are widely expressed. For example, adenosine reduces conduction through the AV node of the heart, slowing heart rate.…”

Section: Astrocytes Cx43 Adenosine and Neuroprotectionmentioning

confidence: 99%

“…123 Adding to the complexity is the fact that the different adenosine receptors may have divergent effects. 119,123,129 For example, knockout of A 2A receptors reduces stroke volume after transient MCAO. 130 Similarly, A 2A agonists increase glutamate release in the brain during ischemia.…”

Section: Astrocytes Cx43 Adenosine and Neuroprotectionmentioning

confidence: 99%

Targeting Astrocytes for Stroke Therapy

2010

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Summary: Stroke remains a major health problem and is a leading cause of death and disability. Past research and neurotherapeutic clinical trials have targeted the molecular mechanisms of neuronal cell death during stroke, but this approach has uniformly failed to reduce stroke-induced damage or to improve functional recovery. Beyond the intrinsic molecular mechanisms inducing neuronal death during ischemia, survival and function of astrocytes is absolutely required for neuronal survival and for functional recovery after stroke. Many functions of astrocytes likely improve neuronal viability during stroke. For example, uptake of glutamate and release of neurotrophins enhances neuronal viability during ischemia. Under certain conditions, however, astrocyte function may compromise neuronal viability. For example, astrocytes may produce inflammatory cytokines or toxic mediators, or may release glutamate. The only clinical neurotherapeutic trial for stroke that specifically targeted astrocyte function focused on reducing release of S-100␤ from astrocytes, which becomes a neurotoxin when present at high levels. Recent work also suggests that astrocytes, beyond their influence on cell survival, also contribute to angiogenesis, neuronal plasticity, and functional recovery in the several days to weeks after stroke. If these delayed functions of astrocytes could be targeted for enhancing stroke recovery, it could contribute importantly to improving stroke recovery. This review focuses on both the positive and the negative influences of astrocytes during stroke, especially as they may be targeted for translation to human trials.

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Adenosine and cerebral ischemia: therapeutic future or death of a brave concept?

Cited by 126 publications

References 231 publications

Adenosine induces hemeoxygenase‐1 expression in microglia through the activation of phosphatidylinositol 3‐kinase and nuclear factor E2‐related factor 2

Adenosine induces hemeoxygenase‐1 expression in microglia through the activation of phosphatidylinositol 3‐kinase and nuclear factor E2‐related factor 2

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

Targeting Astrocytes for Stroke Therapy

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